Daily Endocrinology Research Analysis
Three papers stood out today: a Science study reveals the structural mechanism by which adipogenin stabilizes dodecameric seipin to drive lipid droplet biogenesis; a phase 3 randomized trial shows ropeginterferon alfa-2b outperforms anagrelide in hydroxyurea-intolerant/refractory essential thrombocythaemia; and a JCI Insight study uncovers a selenoprotein (SELENOT) as a central redox regulator of GnRH neuron activity affecting fertility.
Summary
Three papers stood out today: a Science study reveals the structural mechanism by which adipogenin stabilizes dodecameric seipin to drive lipid droplet biogenesis; a phase 3 randomized trial shows ropeginterferon alfa-2b outperforms anagrelide in hydroxyurea-intolerant/refractory essential thrombocythaemia; and a JCI Insight study uncovers a selenoprotein (SELENOT) as a central redox regulator of GnRH neuron activity affecting fertility.
Research Themes
- Structural and mechanistic basis of lipid droplet biogenesis in adipocytes
- Disease-modifying immunotherapy in hydroxyurea-refractory essential thrombocythaemia
- Redox regulation of the hypothalamic-pituitary-gonadal axis via SELENOT
Selected Articles
1. Adipogenin promotes the development of lipid droplets by binding a dodecameric seipin complex.
Using 3.0 Å cryo-EM, the authors show that adipogenin selectively binds dodecameric seipin, bridging subunits to stabilize the complex and promote lipid droplet biogenesis. Gain- and loss-of-function mouse models demonstrate increased adiposity with adipocyte-specific Adig overexpression and impaired triglyceride accumulation in brown fat with Adig deletion.
Impact: This paper defines a structural mechanism for lipid droplet biogenesis with in vivo validation, identifying Adig–seipin interactions as a modulator of lipid storage.
Clinical Implications: While preclinical, these findings nominate Adig–seipin as a potential therapeutic axis for disorders of lipid storage such as lipodystrophy and obesity.
Key Findings
- Cryo-EM structure (~3.0 Å) reveals mammalian seipin forms undecamers and dodecamers; Adig binds selectively to dodecamers.
- Adig bridges and stabilizes adjacent seipin subunits, enhancing complex assembly.
- Adig–seipin complex promotes lipid droplet development at early and late stages.
- Adipocyte-specific Adig overexpression increases fat mass and enlarges lipid droplets in mice.
- Adig deletion impairs triglyceride accumulation in brown adipose tissue.
Methodological Strengths
- High-resolution cryo-EM structural determination of the seipin–Adig complex
- Convergent validation across cell systems and transgenic mouse gain- and loss-of-function models
Limitations
- Preclinical study without human genetic or clinical validation
- Determinants of Adig selectivity for dodecameric seipin and downstream signaling remain to be fully elucidated
Future Directions: Define how Adig expression is regulated in human adipose depots, test therapeutic modulation of Adig–seipin in lipodystrophy/obesity models, and assess human genetic variation at ADIG/SEIPIN loci.
2. Ropeginterferon alfa-2b in hydroxyurea-intolerant or hydroxyurea-refractory essential thrombocythaemia (SURPASS ET): a multicentre, open-label, randomised, active-controlled, phase 3 study.
In 174 randomized patients (96% Asian) with HU-intolerant/refractory ET and leukocytosis, ropeginterferon alfa-2b achieved significantly higher durable modified ELN responses at months 9 and 12 (43% vs 6%) than anagrelide. Grade ≥3 treatment-emergent adverse events and serious adverse events were less frequent with ropeginterferon; cerebral infarctions occurred only in the anagrelide arm, and no treatment-related deaths occurred.
Impact: This phase 3 RCT provides high-level evidence that ropeginterferon alfa-2b is an effective and safer second-line option versus anagrelide for HU-intolerant/refractory ET.
Clinical Implications: For HU-intolerant or -refractory ET with leukocytosis, clinicians should consider ropeginterferon alfa-2b as a second-line therapy given its superior durable responses and favorable safety profile.
Key Findings
- Durable modified ELN responses at months 9 and 12: 43% with ropeginterferon alfa-2b vs 6% with anagrelide (difference 36.5%, p=0.0001).
- Grade ≥3 TEAEs were less frequent with ropeginterferon (23%) than with anagrelide (34%).
- Serious adverse events occurred in 14% (ropeginterferon) vs 30% (anagrelide); cerebral infarction occurred only in the anagrelide group.
- No treatment-related deaths in either group; median follow-up was 12.5 months.
Methodological Strengths
- Multicentre randomized active-controlled phase 3 design with predefined durable response endpoint
- Comprehensive safety assessment and balanced baseline characteristics
Limitations
- Open-label design and relatively short median follow-up (12.5 months)
- Predominantly Asian cohort (96%) may limit generalizability
Future Directions: Longer follow-up to assess thrombotic outcomes, molecular remissions, and durability; head-to-head comparisons with other interferon formulations; and evaluation in broader, more diverse populations.
3. Central SELENOT deficiency impairs gonadotrope axis function, sexual behavior and fertility in male and female mice.
Brain-specific SELENOT deficiency disrupts GnRH neuron redox signaling, elevating GnRH expression and LH, inducing PCOS-like features in females and steroid excess in males, with impaired LH pulsatility and reduced fertility. Pharmacologic GnRH antagonism reverses these phenotypes, positioning SELENOT as a central redox effector of GnRH neuron activity.
Impact: This study uncovers a previously unknown role for a selenoprotein in central reproductive control, linking redox biology to GnRH neuron function and fertility in both sexes.
Clinical Implications: Findings suggest that redox/selenium biology may contribute to disorders such as PCOS and hypothalamic hypogonadism, motivating exploration of biomarkers and targeted interventions; however, translation to humans requires validation.
Key Findings
- Central SELENOT deficiency impairs sexual behavior and reduces fertility in both male and female mice.
- GnRH expression is elevated with excess circulating LH; males show increased steroid hormones and females display a PCOS-like phenotype.
- LH pulse secretion is disrupted in both sexes; administration of a GnRH antagonist reverses the alterations.
- Identifies SELENOT as a redox effector modulating GnRH neuron activity.
Methodological Strengths
- Brain-specific genetic deficiency model with comprehensive endocrine, behavioral, and histological phenotyping in both sexes
- Pharmacologic rescue using a GnRH antagonist demonstrating reversibility and causal pathway
Limitations
- Mouse study without human translational data or clinical correlates
- Molecular link between SELENOT redox activity and GnRH neuron excitability requires further dissection
Future Directions: Probe SELENOT/selenium status in human reproductive disorders, map downstream redox targets in GnRH neurons, and test targeted redox modulation in translational models.